Pegylated interferon is superior to lamivudine (3TC, Epivir) for first-line treatment of chronic hepatitis B virus (HBV) that is hepatitis B `e` antigen-positive – the form of the infection associated with a high level of HBV replication and a high risk of transmission, according to findings of an international study published in the June 30th edition of the New England Journal of Medicine.
Although most people mount an effective immune response to hepatitis B, a small proportion of adults (5-10%) and a high proportion of children (up to 90%) become chronic carriers of the bloodborne infection. People with hepatitis B `e` antigen are highly infectious. The antigen is a sign that HBV is replicating, and the level of HBV activity can be gauged by measuring the amount of HBV DNA in the blood.
The standard endpoints in studies of hepatitis B treatment have been the reduction of liver inflammation and sustained suppression of HBV DNA levels below 100,000 copies/ml. Seroconversion from serum HbeAg positive to negative has been an additional endpoint, but it does not indicate complete clearance of the infection – like HIV, HBV integrates into the host genome. However, seroconversion from positive to negative does indicate a better clinical prognosis.
The first treatment to be licensed for HBV treatment was interferon-alpha, but pegylated interferon was shown to be superior to interferon-alpha in a phase II study. A phase III study compared pegylated interferon with lamivudine, the recommended first line treatment for HBV in Asia. HBV infection is vastly more common in Asia than in Europe or North America.
In the New England Journal of Medicine last week, investigators reported on the study, which randomised 814 HbeAg-positive individuals to receive either pegylated interferon (Pegasys) 180mg once weekly plus placebo, lamivudine 100mg once daily, or a combination of pegylated interferon and lamivudine for 48 weeks. Treatment response was assessed following a 24-week treatment-free follow-up period.
At the end of the follow-up,a total of 32% of patients treated with pegylated interferon achieved HBeAg seroconversion, compared with 19% of those treated with lamivudine, a statistically significant difference (p
A similar pattern was seen with the suppression of HBV DNA below 100,000 copies/ml and with levels of the liver enzyme ALT. Although no significant difference in liver biopsy changes could be detected between groups (the histological response), the investigators did report a significant association between either virologic, biochemical and /or HbeAg response at week 72 and a histological response (p
Lamivudine resistance was significantly more likely to have emerged by week 72 in patients who received lamivudine monotherapy compared to those who received lamivudine with pegylated interferon (27% vs 4%, P
Pegylated interferon treatment was associated with a much higher rate of adverse events (chiefly fever, fatigue, headache) than lamivudine, with approximately three quarters of the interferon group experiencing at least one adverse event (although only 5% in the pegylated interferon arms discontinued treatment). However two patients who received lamivudine alone suffered hepatic decompensation and one subsequently died.
The authors speculate that pegylated interferon showed superiority because it has an immunomodulatory effect as well as an antiviral effect, making it more difficult for resistance to the treatment to develop.
Pegylated interferon (Pegasys) was approved in the European Union and United States for first-line hepatitis B earlier this year on the basis of these results and two other trials.
Lau GKK et al. Peginterferon alfa-2a, lamivudine, and the combination for HbeAg-positive chronic hepatitis B. N Engl J Med 352: 2682-2695, 2005.